Fracture healing and bone repair are postnatal biological processes that closely parallel the ontogenetic events observed during embryonic skeletal development, and these mechanisms have been extensively studied in prior research
1,2. Skeletal tissue repair and fracture healing initiate with an anabolic phase characterized by tissue growth, resulting from stem cell recruitment and differentiation into both skeletal and vascular lineages. Immediately after fracture, a cartilaginous callus forms adjacent to the fracture site as an initial stage of the repair process. Surrounding this central region, the periosteum undergoes hypertrophy at the margins of the newly formed cartilaginous tissue, initiating primary bone formation
3. Concurrently with the development of cartilaginous tissue, progenitor cells destined to form new blood vessels accumulate and differentiate within the surrounding muscle sheath to support the vascularization of the emerging bone
4,5. The expansion of the vascular network surrounding the callus, followed by its invasion into the callus tissue, is evidenced by an increase in blood flow to the site of tissue repair. With the progression of chondrocyte differentiation, mineralization of the cartilage extracellular matrix occurs, culminating in the completion of the anabolic phase of fracture repair via chondrocyte apoptosis
6. The anabolic phase is succeeded by a prolonged period dominated by catabolic activity, characterized by a gradual reduction in the volume of the callus tissue. During this phase, catabolic processes such as cartilage resorption predominate; however, certain anabolic activities also persist. As the cartilage is resorbed, secondary bone formation is initiated, and primary angiogenesis continues to support the replacement of cartilage with newly forming bone tissue. Subsequently, with the initiation of bone remodeling, the primary mineralized matrix is resorbed by osteoclasts, followed by the removal of the secondary bone that was deposited during the cartilage resorption phase
7. As resorption of the bony callus progresses, the process is characterized by coordinated osteoblastic and osteoclastic activity, known as 'coupled remodeling', which remodels the callus back to the original cortical architecture. During this time, the marrow cavity is re-established, and the original marrow composition of hematopoietic tissue and bone is restored. In the final stage of this catabolic phase, extensive vascular remodeling occurs, wherein the expanded vascular network regresses and the elevated blood flow returns to pre-injury levels
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Fasting has been a longstanding practice across diverse cultures, commonly observed during religious rituals (e.g., Ramadan), and also documented historically in contexts such as political hunger strikes, periods of famine, and therapeutic interventions for morbid obesity9. However, over the past 10 to 15 years, short-term fasting has been increasingly adopted as a novel strategy for weight loss and the enhancement of metabolic function. After the release of Michael Mosley’s 2013 book The Fast Diet, the concepts of 'intermittent fasting' (IF) and the '5:2 diet' became increasingly popular in the United Kingdom. Currently, IF is widely practiced as a strategy to reduce energy intake. According to a recent survey, one in four American adults reported having considered or attempted IF10. Furthermore, publications on IF have increased exponentially over the past decade. Current evidence indicates that IF can promote weight loss and confer beneficial health effects, including enhanced insulin sensitivity, improved lipid profiles, and reduced blood pressure11. Unlike conventional diets based on daily caloric restriction, IF involves complete or substantial energy restriction within specific time windows, while allowing adequate or ad libitum food intake during non-restricted periods. Although the health benefits of IF are well-documented, evidence concerning its effects on other physiological systems, particularly the skeletal system, remains limited10. Weight reduction through continuous energy restriction—ranging from mild to severe calorie restriction, with or without micronutrient supplementation—and/or combined with exercise, has been associated with decreases in bone mass and detrimental alterations in bone microarchitecture11. Multiple mechanisms have been suggested to account for these effects, including mechanical unloading, nutrient insufficiencies, and hormonal alterations10. However, it remains uncertain whether IF elicits adverse effects on bone comparable to those observed with other weight loss strategies, or whether distinct characteristics of IF regimens might instead confer benefits for bone healing after fractures. For instance, IF has been hypothesized to influence metabolism by alternating between defined periods of prolonged fasting (catabolic state) and shorter periods of food intake (anabolic state), and/or by aligning eating patterns with endogenous circadian rhythms9. Improved metabolic regulation and enhanced circadian alignment are believed to support skeletal health11. Nevertheless, the cumulative impact of these various features and mechanisms associated with IF on bone remains poorly understood.
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